Varicella zoster virus (VZV), a ubiquitous neurotropic alphaherpesvirus that causes varicella (chickenpox), becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. VZV reactivation, mostly in elderly and immunocompromised individuals, causes zoster, often followed by postherpetic neuralgia, myelitis, meningoencephalitis, vasculopathy and ocular diseases. No other human herpesvirus causes such a wide spectrum of disease. Although zoster vaccine reduces the incidence of zoster by 51.3% within 3 years after immunization, nearly 400,000 Americans still develop zoster every year, of which about 200,000 experience PHN; others develop stroke, paralysis and blindness. None of these neurological disorders would occur if virus reactivation could be prevented. Although the molecular mechanism(s) of VZV reactivation is unknown, VZV is unique in that no less than 12 VZV transcripts are detected in latently infected human ganglia, whereas all other neurotropic alphaherpesviruses, including herpes simplex-1 (HSV-1), transcribe a single latency associated transcript (LAT). HSV-1 LAT facilitates virus reactivation, and its promoter is coated with histones containing post-translational modifications that enhance transcription (euchromatin). Promoters for other HSV-1 genes are bound by modified histones that repress transcription (heterochromatin). The mechanism by which histone modifications are maintained is unknown, but may involve physical separation of histone complexes by chromatin insulators. Overall, the ability of the HSV-1 LAT to facilitate reactivation of latent virus DNA provides a rationale for my hypothesis that one or more VZV genes transcribed in latently infected human ganglia facilitate reactivation of latent VZV through their effects on histone modification. Two specific aims will test our hypothesis. Aim 1 will identify post- translational modifications of histones on promoters of VZV genes expressed during latency. Aim 2 will investigate the mechanism by which euchromatic and heterochromatic histone modification are maintained. We are uniquely qualified to conduct our proposed studies since we have a continuous supply of fresh human ganglia obtained at autopsy, decades of expertise studying both the latent and lytic VZV transcriptome, and have developed ChIP assays and PCR-based multiplex assays to analyze human ganglia latently infected with VZV. Armed with an understanding of the epigenetic regulation of VZV genes, we will be able to design therapeutic agents to combat virus reactivation and mitigate sever neurologic disease in the elderly.